Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: A multicenter randomized controlled trial

Hata et al. BMC Cancer (2017) 17:581
DOI 10.1186/s12885-017-3584-y

RESEARCH ARTICLE

Open Access

Adherence and feasibility of 2 treatment
schedules of S-1 as adjuvant chemotherapy
for patients with completely resected
advanced lung cancer: a multicenter
randomized controlled trial
Yoshinobu Hata1, Takaharu Kiribayashi2, Kazuma Kishi3, Makoto Nagashima4, Takefumi Nakayama5, Shingo Ikeda6,
Mitsutaka Kadokura7, Yuichi Ozeki8, Hajime Otsuka1, Yoshitaka Murakami9, Keigo Takagi1 and Akira Iyoda1*

Abstract
Background: We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically
treated pathological stage IB-IIIA non-small cell lung cancer patients.
Methods: Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1
and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary
endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary
endpoints were relative total administration dose, toxicity, and 3-year disease-free survival.
Results: From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and
assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients
(73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for
arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and
5% of arm B (p = 0.43). Grade 1–3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and
alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate
was 79.0% for arm A and 79.3% for arm B (p = 0.94).
Conclusions: The superiority of feasibility of the shorter schedule was not recognized in the present study. The
conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1

(p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule,
except for grade 1–3 elevation of bilirubin.
Trial registration: This randomized multicenter study was retrospectively registered with the UMIN-CTR
(UMIN000016086, registration date December 30, 2014).
Keywords: Lung cancer, Adjuvant chemotherapy, S-1

* Correspondence:
1
Division of Chest Surgery (Omori), Toho University School of Medicine,
6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License ( which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
( applies to the data made available in this article, unless otherwise stated.


Hata et al. BMC Cancer (2017) 17:581

Background
Lung cancer is the leading cause of cancer-related death
worldwide [1]. During the last decade, adjuvant cisplatinbased chemotherapy has become the standard therapy for
patients with completely resected stage IIA to IIIA non–
small cell lung cancer (NSCLC) [2]. The pooled Lung Adjuvant Cisplatin Evaluation (LACE) study [3] confirmed
that adjuvant chemotherapy achieved a survival benefit of
approximately 5% at 5 years. The Japan Lung Cancer Research Group (JLCRG) trial [4] has shown that postoperative tegafur-uracil (UFT; Taiho Pharmaceutical Co., Ltd.,
Tokyo, Japan) can improve the survival of completely
resected stage I lung adenocarcinoma patients, providing
a significant overall survival advantage of 11% at 5 years

for patients with T2 disease. A meta-analysis of UFT as
postoperative adjuvant chemotherapy [5] for NSCLC
showed that survival rates at 5 years were significantly
higher in patients who received UFT after surgery than in
those who underwent surgery only (82% vs 77%; respectively). A recent analysis reported an overall survival advantage of 6% at 5 years for patients with T1b NSCLC
who received UFT [6], and postoperative adjuvant UFT
for 1 or 2 years has become the standard therapy for patients with completely resected stage IA (> 2 cm) and IB
NSCLC in Japan.
S-1 (Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) is a
second-generation oral fluoropyrimidine composed of
tegafur, gimeracil, and oteracil in a molar ratio of 1:0.4:1
[7]. Postoperative adjuvant chemotherapy with S-1 has
shown significant survival benefit for patients with gastric cancer [8], and S-1 is expected to be a promising
agent for use in an adjuvant setting, with higher antitumor activity than UFT. S-1 has been conventionally prescribed as an oral agent that is administered twice daily
for 4 weeks followed by a 2-week rest period. A treatment schedule that shortened the conventional schedule
by half (2-weeks of administration followed by a 1-week
rest) was reported to be more feasible for patients with
advanced head and neck cancer who had undergone definitive treatment [9]. While the shorter administration
schedule was expected to be more feasible for definitively treated lung cancer patients, the completion rates
of adjuvant S-1 administration for patients with completely resected lung cancer have been reported to be
61%–71% for 6 months with the shorter schedule [10,
11] and 50%–72% for 1-year with the conventional
schedule [12, 13]. The optimal administration schedule
of S-1 in the adjuvant setting for patients with completely resected NSCLC has not yet been investigated.
We therefore performed a multicenter randomized
phase II study, comparing the feasibility of the conventional treatment schedule of S-1 administered for
4 weeks followed by a 2-week rest and the shorter treatment schedule of S-1 administered for 2 weeks followed

Page 2 of 9

by a 1-week rest, as adjuvant treatment of patients with
completely resected NSCLC.

Methods
Eligibility criteria

The criteria for eligibility were as follows: histologically
confirmed primary lung adenocarcinoma, squamous cell
carcinoma, large cell carcinoma, and adenosquamous
carcinoma; complete resection of the primary tumor (R0
resection); pathological stage IB to IIIA disease (TNM version 6); patients aged 20 to 74 years; Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0 or
1; and adequate organ function (leukocyte count of at
least 4000 mm3, absolute neutrophil count of at least
2000 mm3, platelet count of at least 100,000 mm3,
hemoglobin level of at least 9.0 g/dL, aspartate aminotransferase [AST] and alanine transaminase [ALT] levels
lower than 2.5-fold the upper limit of normal, total bilirubin level of 1.5 mg/dL or less, creatinine level lower than
the upper limit of normal, 24-h creatinine clearance rate
of higher than 50 mL/min); able to start within 9 weeks
after surgery; and no prior therapy.
The exclusion criteria were as follows: history of previous chemotherapy, radiotherapy or surgery for lung cancer; pulmonary fibrosis; pleural effusion, ascites, or
cardiac effusion that required drainage; concomitant malignancy; significant comorbidity (poorly controlled angina, myocardial infarction within 3 months, cardiac
failure, poorly controlled diabetes mellitus, severe infection, and others); diarrhea; pregnancy; desiring to have
children; and drug allergy to S-1 or any of its
components.
The study protocol was approved by the local ethics
committee at each participating center. All patients provided written informed consent to participate.
Study design and treatment

The primary endpoints were the rates of completing the

planned administration schedule over 12 months; the
secondary endpoints were relative total administration
dose of S-1, toxicity, and 3-year disease-free survival
(DFS). The completion rates over 12 months were calculated regardless of the presence or absence of dose reduction. The relative total administration dose (relative
dose intensity) was defined as (the actual total dose administered divided by the planned total administered
dose) × 100. Feasibility was evaluated by the completion
rates over 12 months and the relative dose intensity of
S-1. Patient randomization was performed centrally at
the Division of Chest Surgery, Toho University School of
Medicine, Tokyo, Japan, with the following stratification
factors: pathological stage, histology and gender. Sample
size was set to 40 patients to each group, based on the
feasibility. S-1 was administered orally after meals. The


Hata et al. BMC Cancer (2017) 17:581

dosage of S-1 was selected as follows: for a patient with a
body surface area (BSA) < 1.25 m2, 40 mg twice a day
(80 mg/day); BSA of 1.25 m2 or more but <1.5m2, 50 mg
twice a day (100 mg/day); and BSA of 1.5 m2 or more,
60 mg twice a day (120 mg/day). Patients who underwent
complete resection were randomly assigned to either arm
A, S-1 administration for 4 weeks followed by a 2-week rest
period; or arm B, S-1 administration for 2 weeks followed
by a 1-week rest. For both treatment arms, the administration of S-1 was continued for 12 months (8 courses for arm
A and 16 courses for arm B), unless there was any evidence
of recurrence, other malignancies, or severe adverse events.
Lafutidine, a histamine H2 receptor antagonist, was administered at 10 mg twice a day to all the patients to reduce
gastrointestinal toxicities. The patient’s visit was planned at

least every 6 weeks just before the initiation of each course
in A arm or each even course in B arm.
During the study, the dosage of S-1 was adjusted according to the degree of toxicities. The planned dose reduction was from 120 mg to 100 mg, 100 mg to 80 mg,
or 80 mg to 50 mg, for patients with evidence of grade 3
hematological toxicity (except for thrombocytopenia),
grade 2 thrombocytopenia, grade 2 or higher nonhematological toxicity (except for renal dysfunction), or grade
1 renal dysfunction. If a patient receiving a reduced dose
of 50 mg/day continued to manifest or redeveloped toxicity as described, then treatment with S-1 was stopped.

Page 3 of 9

chi-square test. The difference in mean values of the
relative dose intensity of the 2 arms was evaluated using
the Student t-test. The rates of adverse events were
compared by the chi-square test. Three-year DFS were
estimated using the Kaplan–Meier method, and differences between the 2 arms were examined using the logrank test. The level of significance was set at p = 0.05.

Results
Patient characteristics

From April 2005 to January 2012, 80 patients with stage
IB to IIIA NSCLC who had undergone complete resection were enrolled and randomized centrally (39 cases to
arm A and 41 to arm B). After randomization, 2 patients
were found to be ineligible. One arm A patient was histologically diagnosed with pleomorphic carcinoma, and
1 arm B patient was diagnosed with stage IIIB disease
(pT4 with intrapulmonary metastasis). The number of
patients in the intent-to-treat analysis was 38 cases in
arm A and 40 in arm B. The groups were well balanced
with regard to baseline clinical characteristics, surgical
procedures, and histopathological findings (Table 1).

Table 1 Patent characteristics
Arm A
(n = 38)

Male:female, n (%)

26 (68): 12 (32)

25 (63): 15 (37)

0.58

Mean (SD) age, years

62

(6)

63

(9)

0.39

1.59

(0.15)

1.61

(0.18)

0.72

0

36

(95)

37

(92)

1.00

1

2

(5)

3

(8)

26

(68)

24

(60)

Evaluations of feasibility and toxicity

Mean (SD) BSA, m

Feasibility and toxicity analyses were conducted on the
intent-to-treat principle, which included all the patients
in the randomization. Feasibility was evaluated by the
completion rates over 12 months and the relative dose
intensity. The number of patients in each arm was calculated at the time when S-1 administration was reduced
or stopped because of any reasons including an adverse
event associated with S-1, patient refusal, tumor recurrence or other non-S-1-related complication.
The planned duration of follow up of each patient in
each arm was 3 years after randomization. Adverse
events were assessed according to the National Cancer
Institute-Common Terminology Criteria for Adverse
Events v3.0 (CTCAE).

PS, n (%)

Statistical analysis

Our purpose of this study is to compare the feasibility
and toxicity of the short treatment schedule of S-1
(2 week administration with 1 week rest) and the conventional one (4 week administration with 2 week rest).
These comparisons were conducted by the completion
rates over 12 months, relative dose intensity of S-1, and

toxicity. Patient characteristics, feasibility, adverse
events, and disease-free survival were analyzed. The
completion rates over 12 months were compared by the

p

Characteristics

2

Arm B
(n = 40)

Histology, n (%)
Adenocarcinoma
Squamous cell ca.

10

(26)

13

(32)

Large cell carcinoma

2

(5)

2

(5)

Adenosquamous ca.

0

(0)

1

(3)

IB

28

(74)

33

(82)

IIA

2

(5)

0

(0)

IIB

5

(13)

3

(8)

IIIA

3

(8)

4

(10)

Lobectomy

38

(100)

37

(92)

Bilobectomy

0

(0)

1

(3)

Pneumonectomy

0

(0)

1

(3)

Segmentectomy

0

(0)

1

(3)

0.70

Stage, n (%)
0.39

Surgical procedure, n (%)
0.40

BSA body surface area, PS performance status, squamous cell ca. squamous cell
carcinoma, adenosquamous ca. adenosquamous carcinoma; p values for sex,
PS, type of histology, pathological stage, and surgical procedure were
calculated with the use of the chi-square test. p values for age and BSA were
calculated with the use of the Student t-test


Hata et al. BMC Cancer (2017) 17:581

Page 4 of 9

Adenocarcinoma was the most frequent histological subtype, occurring in 68% of arm A and 60% of arm B patients. Pathological stage IB disease was confirmed in 74%
of arm A and 83% of arm B patients. The surgical procedure was lobectomy with mediastinal lymph node resection
in 100% of arm A and 93% of arm B patients. Three arm
B cases (8%) underwent bilobectomy, pneumonectomy, or
segmentectomy with mediastinal lymph node resection.

other non-S-1-related complications). With exclusion
of the censored cases (tumor recurrence and non-S-1related complications), the completion rates were 80%
of arm A and 51% of arm B patients.
The averages of the relative dose intensity over
12 months were 77.2% (95% CI: 68.2%–86.2%) in arm A
and 58.4% (95% CI: 47.3%–69.6%) in arm B patients
(p = 0.01, Table 3).

Feasibility

Adverse events

The completion rates over 12 months were 73.7% (95%
confidence interval [CI] 58.0%–85.0%) in arm A and
45.0% (95% CI: 30.7%–60.2%) in arm B patients
(p = 0.01, Tables 2 and 3). Twenty-eight patients (73.7%)
in arm A (12 patients with dose reduction) and 18 patients (45.0%) in arm B (3 patients with dose reduction,
and 3 patients with delayed courses) received S-1 administration according the planned schedule. S-1 administration was halted because of adverse events or refusal
for 7 (18%) of arm A (n = 6 adverse events, n = 1 refusal) and 15 (38%) of arm B patients (n = 9 adverse
events, n = 6 refusal). S-1 administration was halted because of tumor recurrence or other non-S-1-related
complications for 3 (8%) arm A (n = 1 tumor recurrence, n = 2 non-S-1-related complications) and 7
(18%) arm B patients (n = 4 tumor recurrence, n = 3

Drug-related adverse events are listed in Table 4. The
primary adverse events were hematological, gastrointestinal, and cutaneous signs and symptoms. Adverse
events were recorded for 38 (100%) of arm A patients
(grade 1/2 in 89% and grade 3 in 11%) and 39 (98%) of
arm B patients (grade 1/2 in 93% and grade 3 in 5%;
p = 0.42). Severe grade 3 adverse events were observed
in 4 (11%) arm A patients (elevated bilirubin, neutropenia, and rash) and in 2 (5%) arm B patients (anorexia

and nausea, p = 0.43). Elevated bilirubin, AST, ALT, and
alkaline phosphatase levels were more frequent in arm A
than in arm B patients (p = 0.01, <0.01, 0.01, <0.01, respectively). Two patients, 1 each in arm A and B, died
during the drug administration period, although the
causes death were unknown and were not considered to
be related to S-1 administration.

Table 2 Drug compliance of each course
Arm A (n = 38)

Arm B (n = 40)

Course no.

No. of patients completing
the course

Reason for discontinuation

Course no.

No. of patients completing
the course

Reason for discontinuation

1

36 (94.7%)

Adverse event (2)

1

34 (85.0%)

Patient refusal (3)
Adverse event (3)

2

33 (82.5%)

Patient refusal

3

31 (77.5%)

Patient refusal
Adverse event

4

29 (72.5%)

Recurrence
Changing hospital

5

28 (70.0%)

Adverse event

6

27 (67.5%)

Patient refusal

7

27 (67.5%)

8

25 (62.5%)

Adverse event
Unrelated death

23 (57.5%)

Recurrence (2)

2

34 (89.5%)

3

34 (89.5%)

4

31 (81.6%)

Adverse event (2)

Adverse event (2)
Recurrence

5

31 (81.6%)

9
10

22 (55.0%)

Adverse event

6

31 (81.6%)

11

21 (52.5%)

Adverse event

12

19 (47.5%)

Adverse event
Recurrence
Changing hospital

7

8

30 (78.9%)

28 (73.7%)

Unrelated death

Patient refusal
Changing hospital

13

18 (45.0%)

14

18 (45.0%)

15

18 (45.0%)

16

18 (45.0%)


Hata et al. BMC Cancer (2017) 17:581

Page 5 of 9

Table 3 Feasibility of S-1 administered by 2 schedules
Arm A (n = 38)

Disease-free survival and recurrence
p

Arm B (n = 40)

Completion rate 73.7%
45.0%
(95% CI: 58.0%–85.0%) (95% CI: 30.7%–60.2%)

0.01

Relative dose
intensity

0.01

77.2%
58.4%
(95% CI: 66.8%–87.5%) (95% CI: 47.3%–69.6%)

Arm A: 4 weeks of oral S-1 and a 2-week rest over 12 months; arm B: 2 weeks
of S-1 and a 1-week rest over 12 months; CI confidence interval; p value for
the completion rate was calculated by the chi-square test. p value for the
relative dose intensity was calculated with the use of the Student t-test

The median follow-up time was 64 months (range 6–
113 months). The 3-year DFS rates of arm A and
arm B patients were 79.0% and 79.3%, respectively
(p = 0.94, Fig. 1). A total of 9 (23.7%) arm A and 8
(20.0%) arm B patients relapsed within 3 years. Locoregional recurrence was predominant in both arms; 6
of 9 relapsed arm A and 5 of 8 relapsed arm B patients. The locoregional recurrences in arm A patients
were lung metastases (n = 4), hilar lymph node metastasis (n = 1) and carcinomatous pleurisy (n = 1).
The locoregional recurrences in arm B patients were
lung (n = 2), mediastinal lymph nodes (n = 1) and
carcinomatous pleurisy (n = 1). The distant relapses

Table 4 Drug-related adverse events of S-1 administered by 2 schedules
Arm A (n = 38)
G1/2

p

Arm B (n = 40)
G3

G1/2

G3

n

(%)

n

(%)

n

(%)

n

(%)

31

(82)

1

(3)

26

(65)

0

(0)

0.10

Neutropenia

9

(24)

1

(3)

8

(20)

0

(0)

0.36

Thrombocytopenia

12

(32)

0

(0)

11

(28)

0

(0)

0.81

Hematological

Anemia

27

(71)

0

(0)

23

(58)

0

(0)

0.23

Leukopenia

17

(45)

0

(0)

15

(38)

0

(0)

0.65

Non-hematological

35

(92)

3

(8)

35

(88)

2

(5)

0.21

Elevation of Bilirubin

24

(63)

2

(5)

15

(38)

0

(0)

0.01

Elevation of ALP

16

(42)

0

(0)

6

(15)

0

(0)

<0.01

Elevation of AST

16

(42)

0

(0)

5

(13)

0

(0)

<0.01

Elevation of ALT

15

(39)

0

(0)

3

(8)

0

(0)

0.01

Rash

6

(16)

1

(3)

9

(23)

0

(0)

0.45

Anorexia

14

(37)

0

(0)

12

(30)

2

(5)

0.34

Nausea

15

(39)

0

(0)

14

(35)

1

(3)

0.59

Elevation of BUN

1

(3)

0

(0)

1

(3)

0

(0)

1.00

Elevation of Creatinin

1

(3)

0

(0)

5

(13)

0

(0)

0.20

Pigmentation

12

(32)

0

(0)

15

(38)

0

(0)

0.63

Diarrhea

12

(32)

0

(0)

9

(23)

0

(0)

0.44

General fatigue

6

(16)

0

(0)

10

(25)

0

(0)

0.40

Decline in PS

4

(11)

0

(0)

6

(15)

0

(0)

0.74

Vomiting

4

(11)

0

(0)

3

(8)

0

(0)

0.71

Aphthous stomatitis

3

(8)

0

(0)

6

(15)

0

(0)

0.48

Nervous system disorder

2

(5)

0

(0)

1

(3)

0

(0)

0.61

Edema

2

(5)

0

(0)

2

(5)

0

(0)

1.00

Infection

1

(3)

0

(0)

1

(3)

0

(0)

1.00

Others

6*

(16)

0

(0)

11**

(28)

0

(0)

0.19

34

(89)

4

(11)

37

(93)

2

(5)

0.42

Total

Arm A: 4 weeks of oral S-1 and a 2-week rest over 12 months; arm B: 2 weeks of S-1 and a 1-week rest over 12 months; ALP alkaline phosphatase, AST aspartate
aminotransferase, ALT alanine transaminase, BUN blood urea nitrogen, PS performance status; * = dizziness (1), urticaria (1), lacrimation (1), ileus (1), finger cyanosis
(1), nasal bleeding (1) and dyspnea (1); ** = nasal bleeding (4), taste disorder (2), dizziness (1), fever (1), dry skin (1), finger bleeding (1), lacrimation (1), cutaneous
pruritus (1), blurred vision (1); p values were calculated with the use of the chi-square test. The total number of patients of each arm was used as a denominator
when calculating category-specific percentages in the table


Probability of disease-free survival

Hata et al. BMC Cancer (2017) 17:581

Page 6 of 9

–
–

Arm A (n = 38)
Arm B (n = 40), (p = 0.94)

Years after randomization
Fig. 1 Disease-free survival rate in each arm; 3-year disease-free survival rates were 79.0% in arm A and 79.3% in arm B (p = 0.94, log-rank test)

in arm A patients were brain metastasis (n = 2) and
supraclavicular lymph node metastasis (n = 1) and in
arm B patients were bone metastases (n = 2) and
brain metastasis (n = 1).

Discussion
To the best of our knowledge, this is the first multicenter randomized clinical trial that compared the feasibility
of 2 S-1 administration schedules in a long-term adjuvant setting after curative surgery. This study showed
that the shorter schedule of 2-weeks of S-1 administration and a 1-week rest period resulted in less toxicity
than the conventional schedule of 4-weeks of S-1
followed by 2-weeks rest. But the superiority of the completion rate and relative dose intensity of the shorter
schedule could not be confirmed in the present study.
Before this study was performed, we expected that the
shorter administration schedule would be more feasible
with less toxicity. Because adverse events associated with
S-1 tend to be observed starting 2 to 3 weeks after initiation of S-1 treatment, a shorter administration schedule
was thought to be advantageous. However, the results
showed that the shorter administration schedule was not
superior for the completion rate and the relative total
administration dose. Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1–3 elevation of
bilirubin. The reasons for stopping S-1 for patients taking it according to the shorter schedule included a 23%
adverse event rate and a 17% patient refusal rate, and
the reasons for stopping S-1 for patients taking it according to the conventional schedule included a 16% adverse event rate and a 3% patient refusal rate. Patient

refusal might account for the lower feasibility of the
shorter administration schedule.
Patient compliance is reported to be a problem in
trials of adjuvant chemotherapy [4]. In trials of cisplatinbased chemotherapy that was scheduled to be administered in 3 or 4 cycles postoperatively, only 50%–74% of
the patients completed the planned treatment [14–18].
Even with the infrequent and usually mild adverse reactions of oral UFT, only 61% of patients completed the 2year course [4]. Compliance in trials of adjuvant chemotherapy may not be related to the severity of adverse
events [4]. A feasibility study of adjuvant S-1 for gastric
cancer had a completion rate of 60.7%, with a high rate
of patient refusal due to adverse reactions, especially
after the first course (anorexia) [19]. Based on the results

of the Adjuvant Chemotherapy Trial of S-1 for Gastric
Cancer [8], patients were estimated to refuse S-1 administration even with grade 1 or 2 digestive system adverse
events [20]. In a feasibility study of adjuvant S-1 for elderly patients with NSCLC, both the patients and their
physicians were speculated to be less willing to tolerate
even modest degrees of toxicity, particularly because the
benefits of adjuvant chemotherapy were unproven [10].
Those patients “less willing to tolerate even a modest degree of toxicity” would negatively affect the feasibility of
long-term administration. The shorter S-1 administration schedule in our study had twice the number of administration cycles, and although each cycle consisted of
half the conventional administration dose, the increased
number of cycles might have led to increased opportunities of thinking about refusal.
The completion rates of adjuvant S-1 administered
with a conventional schedule for patients with gastric
cancer have been reported to be 78% for 6 months [8]


Hata et al. BMC Cancer (2017) 17:581

and 61%–66% for 1 year [8, 19]. The completion rates of
S-1 for patients with lung cancer have been reported to
be 61%–71% for 6 months with the shorter schedule [10,
11] and 50%–72% for 1 year with the conventional
schedule [12, 13]. In our study, the completion rates for
1 year were 74% with the conventional schedule and
45% with the shorter schedule. With exclusion of the
censored cases, the completion rates were 80% and 51%,
respectively. Our study found a relatively better completion rate over 1 year with the conventional administration schedule than the other studies. Based on the
assumption that patients will refuse to continue S-1 with
even grade 1 or 2 digestive system adverse events [20],
the prophylactic use of lafutidine, a histamine H2 receptor antagonist, to reduce the occurrence of gastrointestinal toxicities might improve patient compliance. There
has been a recent report on the efficacy of lafutidine for

reducing gastrointestinal toxicity during adjuvant S-1
chemotherapy for patients with gastric cancer [21]. The
rate of patients requiring a dose reduction or interruption of S-1 treatment was significantly lower in the arm
receiving S-1 plus lafutidine than in S-1 alone (30% vs.
83%, respectively).
The 3-year DFS rates were 79.0% for the conventional
S-1 schedule and 79.3% for the shorter schedule, which
were not significantly different. In this study, 78% of the
patients had stage IB disease, and we believe that the 3year DFS of 79.0%–79.3% is acceptable. Tsuchiya et al.
[12] reported comparable results for patients with curatively resected stage IB-IIIA NSCLC who were treated
by adjuvant S-1 administration for 1-year. The 3-year
DFS was 69.4% and the 3-year survival rate was 87.7%.
The 2004 Japanese Lung Cancer Registry Study of
11,663 surgical cases (adjuvant therapy was performed
in 2903 [24.9%] cases and induction chemotherapy in
518 [4.4%] cases) [22] found 3-year survival rates of
79.1% for patients with p-stage IB and 53.7% for patients
with p-stage IIIA disease [23]. Our study should continue to collect additional follow-up survival data, because adjuvant UFT showed relatively delayed survival
benefit after 4 years of follow up [6] and the adjuvant S1 might also show the similar survival benefit. UFT and
its metabolites were reported to have antiangiogenic activity [24], which is considered to be one of the mechanisms for its long-term effectiveness. S-1 shows promise
as an adjuvant chemotherapy that is suitable for longterm administration to outpatient administration, and
has shown higher antitumor activity than UFT. A phase
II trial of S-1 monotherapy as first line treatment for patients with advanced NSCLC found a response rate of
22% [25]. A randomized phase III trial demonstrated
that S-1 plus carboplatin for patients with advanced
NSCLC was noninferior for overall survival, compared
with paclitaxel plus carboplatin [26], regardless of tumor

Page 7 of 9

histology [27]. Another randomized phase III trial demonstrated that S-1 plus cisplatin for patients with advanced NSCLC was noninferior for overall survival,
compared with docetaxel plus cisplatin [28]. Therefore
S-1 is becoming one of the standard chemotherapy regimens for patients with NSCLC in Japan.
Major limitations of our randomized controlled trial
are diagnostic bias of the endpoints and the small study
sample size. Our study was open-label trial and the doctors and patients already knew which regimen they were
allocated. The open-label trial always suffered from the
diagnostic bias and our results was not the exception.
Though feasibility (completion rate) is rather objective
than the toxicity, we should understand that both measures suffered the diagnostic bias in our study. The second issue of our study is its small sample size. The
initiation of this study is April 2005 and patients’ enrollment took 7 years to reach 80 patients. The main reason
for this slow enrollment was the emergence of new
treatment, adjuvant platina doublet for pathological
stage II and IIIA. This treatment was stated as the standard in the guideline for lung cancer in Japan. The introduction of this new treatment affected our enrollment
and the motivation of doctors and patients may be different according to disease stage. The completion rates
over 12 months among pathological stage or among institutions showed no differences.

Conclusions
The superiority of feasibility of the shorter schedule was
not recognized in the present study. The conventional
schedule showed higher completion rates over 12 months
(p = 0.01) and relative dose intensity of S-1 (p = 0.01).
Toxicity showed no significant difference among the
shorter schedule and the conventional schedule, except
for grade 1–3 elevation of bilirubin.
Abbreviations
BSA: body surface area; CI: confidence interval; CTCAE: Common
Terminology Criteria for Adverse Events; DFS: disease-free survival;
ECOG: Eastern Cooperative Oncology Group; NSCLC: non–small cell lung
cancer; PS: performance status

Acknowledgments
We thank the many physicians participating in this trial: Prof. Shinya Kusachi,
Toho University (Ohashi), Tokyo; Prof. Ryoji Katoh, Toho Univeristy (Sakura),
Dr. Kiyohaya Obara, Japan Self-Defense Forces Central Hospital, Tokyo, Dr.
Shigeru Yamamoto, Showa University, Tokyo, and Dr. Aeru Hayashi, International University of Health and Welfare, Tokyo.
Funding
This study was supported in part by JSPS KAKENHI Grant Numbers (C)
JP15K10272, JP26462140. The funding bodies did not play any role in the
design of the study and collection, analysis and interpretation of data nor in
the writing the manuscript.
Availability of data and materials
The datasets supporting the conclusions of this article are included within
the article.


Hata et al. BMC Cancer (2017) 17:581

Authors’ contributions
YH, TK, MN, TN, SI, MK, YO and KT were involved in study design and
interpretation of data. HO and YM performed the statistical analysis. YH
wrote the draft manuscript. TK, KK, MN, TN, SI, MK, YO, KT and AI critically
reviewed the manuscript and provided suggestion for revision. KT and AI
participated in study supervision. All authors read and approved the final
manuscript.

Page 8 of 9

7.

8.

Ethics approval and consent to participate
This prospective study was approved by the local ethics committee of Toho
University Omori Medical Center (assurance no. 26–229), Toho University
Ohashi Medical Center, Toranomon Hospital, Toho University Sakura Medical
Center, Japan Self-Defense Forces Central Hospital, Mitsui Memorial Hospital,
Showa University School of Medicine and National Defense Medical College. All
enrolled patients gave their written informed consents before being registered
in the study. This randomized multicenter study was retrospectively registered
with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

9.

10.

Consent for publication
Written informed consents for publication and presentation of individual
clinical data had been obtained from all the participants.

11.

Competing interests
AI and KK received speaking fee from Taiho. All other authors declare that
they have no competing interests.

12.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details

1
Division of Chest Surgery (Omori), Toho University School of Medicine,
6-11-1 Omori-nishi, Ota-ku, Tokyo 143-8541, Japan. 2Division of Chest Surgery
(Ohashi), Toho University School of Medicine, 2-17-6 Ohashi, Meguro-ku,
Tokyo 153-8515, Japan. 3Department of Respiratory Medicine, Respiratory
Center, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470,
Japan. 4Division of Chest Surgery (Sakura), Toho University School of
Medicine, 564-1 Shimosizu, Sakura, Chiba 285-8741, Japan. 5Department of
Thoracic and Cardiovascular Surgery, Japan Self-Defense Forces Central
Hospital, 1-2-24 Ikejiri, Setagaya-ku, Tokyo 154-8532, Japan. 6Department of
Thoracic Surgery, Mitsui Memorial Hospital, 1 Kandaizumicho, Chiyoda-ku,
Tokyo 101-8643, Japan. 7Division of Chest Surgery, Department of Surgery,
Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo
142-8555, Japan. 8Department of Thoracic Surgery, National Defense Medical
College, 3-2 Namiki, Tokorozawa, Saitama 359-0042, Japan. 9Department of
Medical Statistics, Toho University School of Medicine, 5-21-16 Omori-nishi,
Ota-ku, Tokyo 143-8540, Japan.
Received: 23 October 2016 Accepted: 22 August 2017

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